An epileptic seizure is defined as a clinical event associated with a transient, hypersynchronous neuronal discharge. The seizure represents only the symptom of a potential underlying brain pathology and not the actual disease. Epilepsy, in contradistinction to seizures, is a chronic disorder characterised by recurrent seizures. Epilepsy affects approximately 1% of the population.
Partial-onset seizures are a variety of epileptic seizure which affect only a part of the brain at onset. The seizure often remains localized, but may spread more widely throughout the brain. Partial seizures are generally divided into simple partial seizures, complex partial seizures and partial seizures secondarily generalised.
In contrast, absence seizures, also known as petit mal seizures, are a form of generalized seizure, which affects the whole of the brain, producing abnormal electrical activity throughout both hemispheres and, typically, loss of consciousness. Absence seizures are brief, generalized epileptic seizures with two characteristic features: (1) impairment of consciousness (absence) and (2) particular spike-and-slow wave discharges as measured by electroencephalography (EEG). The clinical manifestations of absence seizure may vary significantly among patients, and their etiology is not well defined or understood. Absence seizures generally occur more frequently in children than adults. Other varieties of generalized seizures include tonic-clonic seizures (grand mal), e.g. primary generalized tonic clonic seizures, myoclonic seizures, atonic seizures, clonic seizures and tonic seizures.
Eslicarbazepine acetate ((S)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide) is a potent voltage-gated sodium channel blocker described, e.g., in WO-A-97/02250, WO-A-2006/121363, WO-A-2007/094694, WO-A-2008/088233, WO-A-2009/054743, WO-A-2011/014084, and WO-A-2011/031176, the contents of which applications are incorporated herein by reference. Eslicarbazepine acetate has been approved by the European Medicines Agency (EMA) for adjunctive therapy for partial-onset seizures, with or without secondary generalization, in adults with epilepsy.
Eslicarbazepine acetate is one of several drugs in the carboxamide dibenzazepine family. Other drugs in this family include oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide, OXC) and carbamazepine (5H-dibenzo[b,f]azepine-5-carboxamide, CBZ).
Drugs in the carboxamide dibenzazepine family are used to treat partial-onset seizures. However, drugs in this class are known to aggravate general seizures, specifically absence seizures. Such aggravation of absence seizures is mediated via enhanced activity at the gamma amino butyric acid (GABAA) receptor. Thus, Liu et al (J Pharmacol Exp Ther 319:790-798) explains that the activity of carbamazepine in aggravating absence seizures arises from the activity of the drug in enhancing activity at the GABAA receptor. Similarly, oxcarbazepine has also been linked with enhanced activity at the GABAA receptor and aggravation of absence seizures (Zheng T et al, Epilepsia, 50(1): 83-87, 2009).
Given that oxcarbazepine and carbamazepine aggravate absence seizures, it was therefore expected that other members of the carboxamide dibenzazepine family, such as eslicarbazepine acetate should not be used to treat patients who suffer from absence seizures. This is explained, for example, in the standard clinicians' reference book “The Treatment of Epilepsy”, 3rd edition, eds. Shorvon, Perucca & Engel, Chapter 38 (Almeida, L et al) (2009), which explains on page 497 that, based on the fact that eslicarbazepine acetate is structurally related to oxcarbazepine and carbamazepine, eslicarbazepine acetate may be expected to be potentially aggravating on some primary seizure types, particularly myoclonic and absence seizures.
Shorvon et al also explain at page 485 that the efficacy spectrum of eslicarbazepine acetate is restricted to partial epilepsies. Thus, there is no expectation in the art that eslicarbazepine acetate would have any effect in treating primary generalized seizures, such as absence seizures and primary generalized tonic clonic seizures. Many of the animal models which have historically been used to test antiepileptogenic properties of compounds are unable to distinguish between efficacy against primary generalized seizures and secondary generalized seizures. Further, many of the animal models may give results which are not directly applicable to the treatment of primary generalized seizures in human patients.
Primary generalized tonic clonic seizures in particular are not well understood, and their mechanism differs from that of secondary generalized tonic clonic seizures. Thus, whilst off label use of drugs licensed exclusively for treating partial seizures has been reported in some secondary generalized seizures, such use has not been reported in primary generalized seizures.